Abstract Age-related neurodegenerative diseases place a substantial and increasing socioeconomic burden on society. Age-related dementias including Alzheimer?s disease represent some of the greatest unmet medical challenges facing the aging population in the US. To date clinical interventions for these diseases have had very modest impact despite major efforts to develop new therapeutics. This landscape suggests that we are still missing fundamental information regarding the root cause of these diseases and the specific cellular vulnerabilities that lead to disease progression. We propose that a critical element of theses disease may relate to local synaptic metabolism. The brain is highly vulnerable from a metabolic point of view: severe hypoglycemia results in overt and severe neurological problems including delirium and coma. Furthermore, as we age (and aging is the strongest correlate of all these afflictions) the efficiency with which we can deliver fuel to tissues (including the brain) and convert this fuel into the useful biochemical currency, the high-energy intermediate adenosine tri-phosphate (ATP), both degrade. Although these neurodegenerative disorders ultimately lead to neuronal death it is thought that much earlier symptomatic problems arise from synaptic dysfunction. My laboratory recently discovered that nerve terminals represent one of the likely loci of the brain?s metabolic vulnerability: they consume large amounts of ATP but store little rapidly usable high-energy molecules and must therefore locally synthesize ATP to maintain function. We also discovered that synapses relay on several mechanisms to upregulate ATP that are essential for synapse function. Additionally, we discovered resting nerve terminals consume large amounts of ATP to maintain the synaptic vesicles proton gradient but that this energy burden likely varies across neurotransmitter type. We propose to test the hypothesis that neurodegenerative diseases have a strong local metabolic component by examining how genetic drivers of neurodegenerative disease specifically impact the local metabolic balance and do to determine if this might be a driver of disease-driven synapse impairment. Although certain neurodegenerative diseases disease initially present with other overt symptoms (for example movement disorders) over time they most frequently convert to dementias in the majority of patients. Here using quantitative approaches we will determine how nerve terminals in a metabolically vulnerable neuron population rely upon glycolysis versus oxidative phosphorylation to support function, examine if maintaining the vesicle proton gradient places a large energetic burden on the nerve terminals (Aim1), determine if the disease mutations associated with mitochondrial integrity specifically impact the balance of ATP (AIM2) and determine if a number of other known disease associated mutations increase metabolic vulnerability by altering the local balance of ATP production versus consumption in this critical neuron population (Aim3). The lessons and insights learned from these studies should then prove valuable in informing the pathology of a larger class of dementias.